The incidence of invasive fungal disease has dramatically increased over the past few decades in parallel with the increase in number of immunocompromised patients (J. D. Noshanchuk. Current Status and Future of Antifungal Therapy for Systemic Mycoses. Recent Patents on Anti-Infective Drug Discovery, 2006, 1, 75-84). Patients with increased risk for severe fungal disease include those undergoing administration of broad-spectrum antibiotics, corticosteroids and cytotoxic agents, intravenous catheters, invasive medical procedures, and Human Immunodeficiency Virus (HIV) infection.
Toxicity presents one barrier to effective antifungal therapy. An additional factor limiting the effectiveness of antifungal therapy is resistance. Resistance to antifungal therapeutics can result from expression of efflux pumps which reduce drug accumulation, alteration of target proteins, and modification of membrane sterol composition (Sanglard D, Odds F C. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002; 2(2): 73-85).
The clinical consequences of antifungal resistance are evident in treatment failures as well as in the changing prevalence of fungi, such as for Candida spp. and emerging moulds, causing disease (Baddley J W, Pappas P G. Antifungal combination therapy: clinical potential. Drugs 2005; 65(11): 1461-80, Nucci M, Marr K A. Emerging fungal diseases. Clin Infect Dis 2005; 41(4): 521-6. Epub 2005 Jul. 11). Candida spp. are the fourth most common cause of bloodstream infection in the U.S. (Wisplinghoff et al., Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39(3): 309-317) with an attributable mortality rate of approximately 40% (Gudlaugsson O, Gillespie S, Lee K, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003; 37(9): 1172-7. Epub 2003 Oct. 8). Currently, the incidence of aspergillosis in the US ranges from 0.5% after autologous hematopoietic stem cell transplantation to 3.9% after transplantation from an unrelated donor (Morgan J, Wannemuehler K A, Marr K A, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol 2005; 43(Suppl 1): S49-58). In these patients, mortality 3 months after diagnosis of aspergillosis was 53.8% in autologous transplant recipients and 84.6% in those with unrelated donor transplants (Morgan J, Wannemuehler K A, Marr K A, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol 2005; 43(Suppl 1): S49-58).
These data clearly show the need for new approaches to combating systemic mycoses, which could be effective in humans. Moreover, fungus-specific interventions could prove valuable in combating infections in other animals as well as plants.